The pathogenesis of the liver cell necrosis produced in the intact rat and in primary cultures by galactosamine, phallodin, bromobenzene and acetoaminophen are being studied. In each case the cell killing is dependent upon the concentration of calcium ions in the extracellular fluids, and it is our working hypothesis that each of the agents ultimately leads to plasma membrane injury that disrupts the maintenance of intracellular calcium homeostasis with a resultant influx of these ions and cell death. We are, therefore, focusing on the nature of plasma membrane injury produced in each case. With galactosamine, we are currently investigating the alpha-adrenergic receptors in galactosamine-intoxicated cells. With phalloidin, we are concerned with the relationship between actin microfilaments and the structural organization of membrane lipids. With bromobenzene and acetoaminophen, we are attempting to assess the relative roles of the covalent binding of reactive metabolites and the peroxidation of membrane lipids in the generation of lethal plasma membrane injury.